Disorders of energy metabolism and overweight/obesity are extremely common. Up to 48% of Veterans are overweight and 24% are obese, a higher incidence than that of the general US population. Reductions in physical activity levels as well as an increase in the consumption of energy-dense food have paralleled the increase in obesity prevalence. It is crucial to find approaches to prevent and treat obesity and related health problems. ! Evidence suggests that physical exercise can improve appetite function, so that body weight is better controlled. In addition to increasing energy expenditure (calories burned), exercise is known to reduce appetite. Changed signaling in a brain site (the hypothalamus) has been proposed as a possible mechanism underlying exercise-induced reductions in feeding. We hypothesize that BDNF (brain derived neurotrophic factor), a brain chemical, is involved in exercise-induced feeding reduction. ! We have found that exercise and BDNF share some common effects, as both reduce food intake and body weight, and increase energy expenditure. The amount of BDNF in the hypothalamus seems to affect feeding and energy expenditure: with an increase (or decrease) in hypothalamic BDNF, food consumption is decreased (or increased) whereas energy expenditure is increased (or decreased), respectively. In rats, an increase in running elevates BDNF in hypothalamus. Exercise increases hypothalamic BDNF and BDNF-containing cells (neurons) compared to sedentary animals. After we chronically injected BDNF in hypothalamus of rats, there was new cell growth in hypothalamus. This suggests exercise may promote new cell growth by increasing BDNF production. However, the identities of the new cells and the impact of these new cells on energy regulation need to be explored. ! We hypothesize that BDNF mediates exercise-associated reductions in food intake, increases in energy expenditure, and improvement of brain function, and that exercise induces new nerve cells that contribute to regulation of energy balance. To test these ideas, we propose these aims: ! Aim 1. Exercise increases BDNF action in hypothalamus, reducing food intake and body weight. In this aim we will test whether exercise increases BDNF action and reduces food intake, and whether BDNF is necessary for exercise induced feeding reduction. ! Aim 2. Exercise improves hypothalamic function via BDNF. In this aim we will test whether exercise improves function of the hypothalamus, mainly by increasing growth of new nerve cells, and whether BDNF is necessary for exercise-induced cell growth. ! Aim 3. Exercise induced hypothalamic new cells contribute to energy balance regulation. In this aim we will test whether exercise-induced new cells contribute to feeding reduction and energy expenditure increase, determine the identities of the newly developed cells, and whether the exercise-induced new cells respond to proteins important to body weight regulation. ! The results gained will help our efforts in obesity prevention and treatment in our Veteran population.